Laboratory of Innovative Toxicological Research and Analyses, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszow, Poland.
Department of Regulatory and Forensic Toxicology, Institute of Medical Expertises, Łódź, ul. Aleksandrowska 67/93, 91-205 Łódź, Poland.
Int J Environ Res Public Health. 2023 Feb 2;20(3):2701. doi: 10.3390/ijerph20032701.
Potential heavy metal impurities (HMI) in pharmaceuticals/pharmaceutical products/drugs based on plant raw materials (e.g., herbs) are an important problem in the pharmaceutical industry; however, there is a lack of scientific articles on the comprehensive toxicological risk assessment of HMI in ointment applied dermally. To make the appropriate toxicological risk assessment, we consider: (1) the raw results of the levels of lead and cadmium in the ointments (metal per kg of mass), (2) one-time administration of the applied ointment, (3) daily exposure of Pb and Cd in the applied ointments according to the maximum daily dose of applied pharmaceuticals, including transcutaneous penetration, (4) human health risk assessment based on the USEPA model, and 5) the margin of exposure (MoE). The raw results indicated that lead (7.05-101.78 µg/kg) and cadmium (0.32-0.81 µg/kg) were present in all samples. The levels of analyzed HMI (independently of the producer and declared composition) were similar. Pb and Cd contamination associated with daily doses met the standards of the ICH Q3D (R2) guide on elemental impurities in pharmaceuticals, including the cutaneous route of administration. Taking into account the daily amount of lead and cadmium (ointment, ug/day) the results were satisfactory, confirming the safety of marjoram herb extract ointments available in Polish pharmacies according to the ICH guideline Q3D (R2) on elemental impurities. The HQ values obtained for Pb and Cd in all samples were less than 1; therefore, exposure to these HMI would not cause a health risk based on the USEPA model strategy. Furthermore, the obtained values of MoE for Pb and Cd in ointments were above 100, so exposure to these elements would not cause a health risk based on the MoE-based strategy. The original contribution of this work is that this is the first study on the triple approach strategy to evaluate the safety of heavy metal impurities in traditional herbal medicinal products applied dermally in solid form (ointments with marjoram herb extract). The research is novel and has not been previously published; The proposed procedure includes transcutaneous penetration of heavy metal (Pb and Cd) impurities described for the first time in the literature.
基于植物原料（例如草药）的药物/药品中的潜在重金属杂质（HMI）是制药行业的一个重要问题；然而，关于透皮应用软膏中 HMI 的全面毒理学风险评估的科学文章却很少。为了进行适当的毒理学风险评估，我们考虑了以下因素：（1）软膏中铅和镉含量的原始结果（每公斤质量的金属），（2）一次施用软膏，（3）根据最大每日施用药物剂量，包括经皮渗透，每日暴露于 Pb 和 Cd，（4）基于 USEPA 模型的人类健康风险评估，以及（5）暴露限度（MoE）。原始结果表明，所有样品中均存在铅（7.05-101.78μg/kg）和镉（0.32-0.81μg/kg）。分析的 HMI 水平（与生产商和申报成分无关）相似。与每日剂量相关的 Pb 和 Cd 污染符合 ICH Q3D（R2）制药中元素杂质指南的标准，包括经皮给药途径。考虑到铅和镉的每日用量（软膏，ug/天），结果令人满意，根据 ICH 指南 Q3D（R2）关于元素杂质，证实了波兰药店出售的马郁兰草药提取物软膏的安全性。所有样品中获得的 Pb 和 Cd 的 HQ 值均小于 1；因此，根据 USEPA 模型策略，暴露于这些 HMI 不会引起健康风险。此外，软膏中 Pb 和 Cd 的 MoE 值均大于 100，因此根据基于 MoE 的策略，暴露于这些元素不会引起健康风险。这项工作的原创贡献在于，这是首次应用三重方法策略评估透皮应用（马郁兰草药提取物软膏）的传统草药药物中重金属杂质安全性的研究。该研究是新颖的，以前没有发表过；所提出的程序包括重金属（Pb 和 Cd）杂质的经皮渗透，这在文献中是首次描述的。
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